Over two million children in Africa will die of malaria this year. To control malaria, several vaccine approaches are being developed, one of which is against the sexual stages (aka a transmission-blocking vaccine). The genes encoding four potential transmission-blocking target antigens (Pfs25, Pfs28, Pfs40, and Pfs230) of transmission-blocking antibodies have now been cloned in our laboratory, and a fifth, a parasite-produced chitinase, and a sixth, a mosquito-produced protease, have been identified. Of the four target antigens that have been cloned, all have been expressed in one or more recombinant expression systems. rPfs25, r Pfs28 and rPfs230 have induced transmission-blocking antibodies in laboratory animals. Our immediate goals are to 1) test in humans the safety, immunogenicity, and efficacy of a rPfs25 subunit vaccine and design a means of testing the efficacy of such a transmission-blocking vaccine in the field, 2) improve expression of the rPfs28 that induces blocking antibodies and test various combinations of rPfs25 and rPfs28 in a cocktail vaccine suitable for use in humans to determine if the combination elicits longer lasting or higher titer transmission-blocking antibodies, 3) determine the role, if any, that the calcium-binding Pfs40 plays in sexual development and ascertain if Pfs40 is a target of transmission-blocking antibodies, 4) improve the expression of rPfs230 so that it induces antibodies equivalent to those of transmission- blocking mAbs to Pfs230, 5) isolate and express the genes encoding the parasite-produced chitinase and mosquito-produced proteases, and 6) isolate analogous genes to the five parasite proteins, if they exist, from P. vivax. Our more long-term goals include identifying new target antigens on sexual stage parasites, and defining the molecular mechanisms involved in fertilization of malarial parasites.